Ankylosing Spondylitis—Axial Spondyloarthritis

By Muhammad Asim Khan, Nurallah Akkoc and MD

Ankylosing spondylitis (AS) and related forms of spondyloarthritis (SpA) are, as a group, as common as rheumatoid arthritis (RA). Their presenting clinical manifestations are wide-ranging and heterogeneous, and the patients end up seeing a variety of medical and surgical health care professionals before they get diagnosed. Early diagnosis and effective management can mitigate the severity of the disease, and make a meaningful difference in the lives of these patients.

This book provides evidence-based, practical information on all aspects of AS - Axial SpA, with emphasis on clinical features, pointers for early diagnosis, and comprehensive coverage of current treatment options, including the latest biologic therapies.

• Language: English
• Publisher: Professional Communications, Inc
• Release date: Oct 13, 2023
• ISBN: 9781545756867

Book preview

CHAPTER 1

Introductory Overview

I (MAK) am very pleased that, with the help of my co-author (NA), we have been able to finish the third edition of this book in year 2023. We hope that rheumatologists, internists, physiatrists, and other specialists, as well as researchers, trainees, physical therapists, physician assistants, nurse practitioners, and other healthcare providers will find this book to be clinically useful.

This book deals with axial spondyloarthritis (axSpA) that encompasses ankylosing spondylitis (AS) and spondylitic disease without radiographic evidence of sacroiliitis that is currently termed non-radiographic axSpA (nr-axSpA).¹-⁵ Together they form the predominantly axial subgroup of spondyloarthritis (SpA), whereas psoriatic arthritis (PsA), enteropathic arthritis (associated with Crohn’s disease [CD] and ulcerative colitis [UC]), reactive arthritis, and undifferentiated SpA form the predominantly peripheral subgroup of SpA (Figure 1.1). These diseases show a strong association with HLA-B27, but the strength of this association varies among these various forms and among some of the racial/ethnic groups worldwide.¹-⁴

For many years, AS/axSpA was considered to be a predominantly male disease but a relatively recent study from Switzerland, shows that the male to female ratio has declined from 2.57:1 in 1980 to 1.03:1 by the end of 2016.⁶ Although the age of onset of AS is similar, women have a significantly longer delay in diagnosis, and a significantly lower TNFi efficacy and drug survival. Men show a little stronger association with HLA-B27 and a higher radiographic progression, but the disease burden is similar between males and females.⁷

AS is the prototypic form of SpA with potentially most severe outcome and is characterized by predominantly axial skeletal symptoms and radiographic evidence of sacroiliitis, as defined by the modified New York (mNY). For practical purposes it has been also called radiographic axSpA (r-axSpA), as discussed in Chapter 5. The typical sites of inflammation are the entheses and synovio-entheseal complex where ligaments and tendons insert into bone and form sites of high biomechanical stress.³ This is also accompanied by reactive osteitis, periostitis, and osteoproliferation. The wide spectrum of musculoskeletal features is shown in Figure 1.2, and axSpA also may be accompanied by many extraskeletal manifestations, the commonest of them being acute anterior uveitis, and co-morbid conditions (Figure 7.1). Figure 1.3 shows the wide clinical spectrum of axSpA.

The key pathological element is enthesitis, but sacroiliitis is the main diagnostic feature of AS/axSpA. Diagnostic criteria for spondylitic disease that encompasses AS were proposed in 1987 but they have not as yet been validated⁸ (Table 11.2). In the absence of any validated diagnostic criteria, clinicians sometimes inappropriately use the Assessment of Spondyloarthritis International Society (ASAS) classification criteria for axSpA for diagnosis,⁹,¹⁰ and this is unfortunately perpetuated in part by the statement in the abstract of the original paper describing the final selection of these criteria that they may help rheumatologists in clinical practice in diagnosing axSpA in those with chronic back pain.¹¹ The diagnostic approach in clinical practice is aimed at the estimation of the probability of a suspected disease based on the patient’s clinical history, physical examination, investigations, and the exclusion of alternative explanations that are not included in the ASAS classification criteria.³,⁹

There is still 3 to 10 years (mean 6 years) delay between onset of axSpA and its final diagnosis, and as discussed in Chapter 11, it is hoped that advances in our understanding of its biology via novel imaging, genetic, and biomarker studies will probably enable the resolution of many current issues and facilitate early diagnosis that is sorely needed now that there has been substantial progress made in its treatment. However, when compared with rheumatoid arthritis (RA), the treatment options for AS/axSpA are relatively limited, although the choices are expected to increase. A set of recommendations for the treatment of AS and nr-axSpA, developed as a joint effort by the American College of Rheumatology (ACR), the Spondylitis Association of America (SAA), and the Spondyloarthritis Research and Treatment Network (SPARTAN), has recently been updated.¹²

The strong genetic association of AS with HLA-B27 has been known for 48 years, and by now more than 100 additional disease predisposing genetic loci have been discovered, and some of them are shared between AS, UC, and CD.¹³-¹⁵ Intestinal inflammation, observed in >60% of patients with AS, intestinal microbial dysbiosis, and Th17 immunity are all linked to the pathophysiology of this disease, and the gut inflammation is characterized by an overexpression of IL-23 and possibly other cytokines that regulate lamina propria NKp44(+) natural killer (NK) cells that appear to play a tissue-protective role.¹³,¹⁵,¹⁶

A truly remarkable study was published by Sherlock and associates in 2012¹⁷ (discussed in Chapter 4), the results of which were well summarized in a figure by Lories and McInnes¹⁸ (Figure 4.10) that demonstrated that an excess of IL-23 is sufficient in generating specific prototypic SpA manifestations because mice injected with IL-23 genetic mini-circles (to overexpress IL-23) develop enthesitis and subsequently arthritis (including sacroiliitis), osteoproliferation, psoriasis, and inflammation of the aortic root.¹⁷,¹⁹ Expression of inflammatory genes (eg, TNF-α, IL-6, chemokines, and matrix metalloproteinases) was observed in the inflamed paws, but TNF blockers did not inhibit development of this IL-23–mediated disease. Inflammation occurred independently of the classic CD4+ Th17 cells. Rather, IL23R+RORyt+ CD4-CD8- innate lymphoid-like T cells were found to be residing in both the entheses and the aortic root. Remarkably, treatment of these mice with anti-IL-17 or anti-IL-22 ameliorated enthesitis and arthritis, but it was most effective when given in combination.¹⁸ IL-23 and Th17 signature cytokines (IL-17 and IL-22) thus provide another link between mucosal and joint immunity. IL-23 and IL-17 expression has been reported to be upregulated in the gut, peripheral blood, and synovium of SpA patients.²⁰ IL-23 mediates inflammatory process through IL-17 and TNF, while IL-22 predisposes to new bone formation. Recently, a novel pathogenetic model has been proposed which postulated that changes in the local metabolic environment (pH, salt) may play a key role in the development of AS by induction of a Th17 pro-inflammatory phenotype through activation of glycosphingolipid sensors (encoded by the GPR genes – in particularly GPR65) and serum and glucocorticoid-regulated kinase-1 (SGK1) (Figure 4.11).²¹

Anti-IL-12/23 P40 monoclonal antibody, ustekinumab, has been approved for the treatment for psoriasis and PsA. and IL-17 inhibitors (IL-17is) secukinumab and ixekizumab have now been approved by both the Food and Drug Administration (FDA) and European Medicines Agency (EMA) for the treatment of psoriasis, PsA, and AS.²²-²⁷ Since the release of the first edition of this book, the FDA approved certolizumab pegol, secukinumab, and ixekizumab to treat nr-axSpA, based on the studies conducted using designs addressing the key concerns raised by the FDA in the past, after reviewing the initial application files of adalimumab and certolizumab submitted for approval for the indication of nr-axSpA.²⁸-³²

Janus kinase inhibitors (JAKis) have been used for the treatment of RA as the latest drug class of disease-modifying category. This class of drugs are now emerging as new potential therapeutics for AS, after the successful results obtained in phase 2 and phase 3 trials of tofacitinib (pan-JAK inhibitor), upadacitinib (selective JAK1 inhibitor) and filgotinib (selective JAK1 inhibitor) in AS.³³-³⁶ Their efficacy appears to be comparable to each other as well as to the available biologics drugs, which unfortunately loose efficacy or fail in a considerable number of patients with AS. Upadacitinib has just been approved in the European Union (EU) countries for the treatment of adults patients with active AS (who have responded inadequately to conventional therapy) and active PsA (who had inadequate response or are intolerant to one or more DMARDs).³⁶ It is hoped that JAKis can address some of the unmet need in the treatment of such patients, if the recent safety concerns raised by the FDA regarding the increased cardiovascular and cancer adverse events associated with tofacitinib relative to TNF inhibitors observed in RA patients can be resolved.³⁷,³⁸ Drug maker of filgotinib has paused the two ongoing phase 3 trials for AS upon the request of additional safety data by the FDA regarding the testicular toxicity of the drug in RA trials.³⁹

REFERENCES

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6.Baumberger H, Khan M. SAT0417 Gradual progressive change to equal prevalence of ankylosing spondylitis among males and females in switzerland: data from the swiss ankylosing spondylitis society (SVMB). Ann Rheum Dis. 2017;76(suppl 2):929-929.

7.Rusman T, van Bentum RE, van der Horst-Bruinsma IE. Sex and gender differences in axial spondyloarthritis: myths and truths. Rheumatology (Oxford). 2020;59(suppl 4):iv38-iv46.

8.Cats A, Van der Linden SJ, Goei The HS, Khan MA. Proposals for diagnostic criteria of ankylosing spondylitis and allied disorders. Clin Exp Rheumatol. 1987;5(2):167-171.

9.Khan MA, van der Linden S. Axial spondyloarthritis: a better name for an old disease: a step toward uniform reporting. ACR Open Rheumatol. 2019;1(5):336-339.

10.Robinson PC, van der Linden S, Khan MA, Taylor WJ. Axial spondyloarthritis: concept, construct, classification and implication for therapy. Nat Rev Rheumatol. 2021;17(2):109-118.

11.Rudwaleit M, van der Heijde D, Landewe R, et al. The development of Assessment of SpondyloArthritis International Society classification criteria for axial spondyloarthritis (part II): validation and final selection. Ann Rheum Dis. 2009;68(6):777-783.

12.Ward MM, Deodhar A, Gensler LS et al. 2019 Update of the American College of Rheumatology/Spondylitis Association of America/Spondyloarthritis Research and Treatment Network Recommendations for the Treatment of Ankylosing Spondylitis and Nonradiographic Axial Spondyloarthritis. Arthritis Rheumatol. 2019;71(10):1599-1613.

13.Brown MA, Kenna T, Wordsworth BP. Genetics of ankylosing spondylitis—insights into pathogenesis. Nat Rev Rheumatol. 2016;12(2):81-91.

14.Ellinghaus D, Jostins L, Spain SL et al. Analysis of five chronic inflammatory diseases identifies 27 new associations and highlights disease-specific patterns at shared loci. Nat Genet. 2016;48(5):510-518.

15.Wordsworth BP, Cohen CJ, Vecellio M. Quantifying the genetic risk for the development of axial spondyloarthropathy: could this become a diagnostic tool? Curr Opin Rheumatol. 2018;30(4):319-323.

16.Berlinberg AJ, Regner EH, Stahly A, et al. Multi ‘Omics analysis of intestinal tissue in ankylosing spondylitis identifies alterations in the tryptophan metabolism pathway. Frontiers Immunol. 2021;12.

17.Sherlock JP, Joyce-Shaikh B, Turner SP et al. IL-23 induces spondyloarthropathy by acting on ROR-gammat+ CD3+CD4-CD8- entheseal resident T cells. Nat Med. 2012;18(7):1069-1076.

18.Lories RJ, McInnes IB. Primed for inflammation: enthesis-resident T cells. Nat Med. 2012;18(7):1018-1019.

19.Sherlock JP, Taylor PC, Buckley CD, Cua DJ. Spondyloarthropathy: interleukin 23 and disease modification. Lancet. 2015;385(9982):2017-2018.

20.Ciccia F, Guggino G, Rizzo A et al. Type 3 innate lymphoid cells producing IL-17 and IL-22 are expanded in the gut, in the peripheral blood, synovial fluid and bone marrow of patients with ankylosing spondylitis. Ann Rheum Dis. 2015;74(9):1739-1747.

21.Voruganti A, Bowness P. New developments in our understanding of ankylosing spondylitis pathogenesis. Immunology. 2020;161(2):94-102.

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30.Deodhar A, Gensler LS, Kay J et al. A fifty-two-week, randomized, placebo-controlled trial of certolizumab pegol in nonradiographic axial spondyloarthritis. Arthritis Rheumatol. 2019;71(7):1101-1111.

31.Deodhar A, van der Heijde D, Gensler LS, et al. Ixekizumab for patients with non-radiographic axial spondyloarthritis (COAST-X): a randomised, placebo-controlled trial. Lancet. 2020;395(10217):53-64.

32.Deodhar A, Blanco R, Dokoupilova E et al. Improvement of signs and symptoms of nonradiographic axial spondyloarthritis in patients treated with secukinumab: primary results of a randomized, placebo-controlled phase III study. Arthritis Rheumatol. 2021;73(1):110-120.

33.van der Heijde D, Song I-H, Pangan AL et al. Efficacy and safety of upadacitinib in patients with active ankylosing spondylitis (SELECT-AXIS 1): a multicentre, randomised, double-blind, placebo-controlled, phase 2/3 trial. Lancet. 2019;394(10214):2108-2117.

34.van der Heijde D, Baraliakos X, Gensler LS et al. Efficacy and safety of filgotinib, a selective Janus kinase 1 inhibitor, in patients with active ankylosing spondylitis (TORTUGA): results from a randomised, placebo-controlled, phase 2 trial. Lancet. 2018;392(10162):2378-2387.

35.Deodhar A, Sliwinska-Stanczyk P, Xu H, et al. Tofacitinib for the treatment of ankylosing spondylitis: a phase III, randomised, double-blind, placebo-controlled study. Ann Rheum Dis. 2021.doi: 10.1136/annrheumdis-2020-219601.

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37.Pfizer Shares Co-Primary Endpoint Results from Post-Marketing Required Safety Study of Xeljanza (tofacitinib) in Subjects with Rheumatoid Arthritis (RA). https://www.pfizer.com/news/press-release/press-release-detail/pfizer-shares-co-primary-endpoint-results-post-marketing. Accessed March 2, 2021.

38.FDA Drug Safety Communication. Safety trial finds risk of blood clots in the lungs and death with higher dose of tofacitinib (Xeljanz, Xeljanz XR) in rheumatoid arthritis patients; FDA to investigate (Xeljanz, Xeljanz XR). US Food and Drug Administration. www.fda.gov/drugs/drug-safety-and-availability/fda-approves-boxed-warning-about-increased-risk-blood-clots-and-death-higher-dose-arthritis-and. Accessed March 23, 2021.

39.Gilead and Galapagos Announce New Commercialization and Development Agreement for Jyseleca (filgotinib). Press release. December 15, 2020. https://www.gilead.com/news-and-press/press-room/press-releases/2020/12/gilead-and-galapagos-announce-new-commercialization-and-development-agreement-for-jyseleca-filgotinib. Accessed March 23, 2021.

CHAPTER 2

Classification Criteria

Classification criteria are designed to define for clinical and epidemiological studies a highly disease-specific group of patients.¹ The first criteria for AS were based on the clinical experience of rheumatologists at a meeting held in Rome in Italy in 1961, but since then our understanding of the disease demographics has been changing resulting in subsequent revisions and also new criteria that are all listed in Table 2.1.²-¹⁴ Thus the Rome criteria were revised at a meeting in New York in the US in 1996 by removal of thoracic pain and uveitis that were deemed to have low specificity or sensitivity, resulting in the New York criteria.⁵

Incorporation of criteria for chronic inflammatory back pain, as proposed by Calin and colleagues in 1977 (Table 2.2),⁶ resulted in mNY criteria, first proposed in 1983,⁷ and published a year later.⁸ They are the most widely used validated criteria to classify AS, with 98% specificity and 83% sensitivity. According to these criteria, a patient can be classified as having definite AS in the presence of at least one of the clinical features (inflammatory back pain, limitation of mobility of the lumbar spine, or limitation of chest expansion) and the radiologic evidence of definite sacroiliitis.

Diagnostic criteria for AS have also been proposed but they have not been properly validated.⁹,¹⁰ Amor Criteria (Table 2.3),¹² published in 1990, and the European Spondyloarthropathy Study Group (ESSG) criteria published a year later (Table 2.4),¹¹ were developed encompassing the wider clinical spectrum of SpA that facilitate earlier disease recognition.¹³

The availability of MRI with its ability to detect early inflammatory changes in the sacroiliac joint for early recognition of axSpA, the advent of new and more effective therapies, and the need to separately identify axial and peripheral forms of SpA were the reasons for the most recently proposed criteria by the ASAS classification criteria for axSpA in 2009 (Table 2.1) and 2 years later for peripheral SpA.¹⁴

The ASAS axSpA criteria were developed using a cohort of 649 patients with chronic back pain referred to rheumatologists for suspicion of axSpA. The initial criteria based on roughly 40% of the cohort were subsequently validated by using the remainder (60%) cohort, utilizing expert rheumatologists’ opinions. The final criteria for axSpA, the concise form of which is shown in Table 2.5, is based on two sets. One set utilizes the clinical and imaging (by conventional pelvic radiography or by MRI) findings and the other is based on the HLA-B27 status and the clinical findings.

The presence of sacroiliitis (by radiography or by MRI) plus at least one SpA feature (imaging arm) or the presence of HLA-B27 plus at least two SpA features (clinical arm) has 82.9% sensitivity and 84.4% specificity. ASAS has also developed and evaluated the accuracy of the new classification criteria and compared them with the ESSG and the Amor criteria, using the opinion of an expert panel as the reference standard. The ASAS criteria had a sensitivity of 77.8% and a specificity of 82.9%. The modified ESSG criteria had a sensitivity and a specificity of 62.5% and 81.1%, respectively, and the Amor criteria had a sensitivity and a specificity of 39.8% and 97.8%, respectively.¹⁵

The accuracy of the imaging-arm of the ASAS criteria alone was studied in a case-control study of 48 patients with and without rheumatologist-diagnosed SpA found a sensitivity of only 66% but a specificity of 94%.¹⁶ On the other hand, as mentioned earlier, the mNY criteria set for classification of AS is very highly specific (98% specificity) and very useful clinically if the criteria set is met; but it is not sensitive enough (83% sensitivity) to encompass all patients with AS.⁸ The positive predictive value of the confirmation of the initial diagnosis of axSpA after 3 to 5 years of follow-up has been found to be over 90%.¹⁷

The complex multi-arm selection design of the ASAS classification criteria introduces considerable heterogeneity between patients with radiographic and nr-axSpA, and between the imaging and the clinical arm.¹⁸ Application of MRI of the SI joints (SIJ) has resulted in a considerably higher prevalence rate of axSpA, along with a higher proportion of females and a lower prevalence figures for HLA-B27 among people classified as axSpA.¹⁹ Data suggest misclassification bias can result in some chronic back pain patients getting falsely labeled as suffering from axSpA. Moreover, the criteria lack, in particular, construct and content validity.¹⁹ Suggestions regarding how to improve the ASAS criteria have been published,¹⁹ and attempts are underway to improve this criteria set. However, it can be stated that these new criteria may enable early recognition of axSpA in patients who present with chronic back pain with onset before age 45, but only after other causes for the patient’s clinical presentation have been excluded.

AxSpA seems to progress to radiographic sacroiliitis relatively more slowly in women than in men. Therefore, among patients classified as nr-axSpA by the ASAS criteria, women comprise >50% of the patients. This confirms the original observation published more than 36 years ago that that women relatively more often present with spondylitic disease without radiographic evidence of sacroiliitis.²⁰ The term non-radiographic is currently used to describe this form of axSpA, but it has not been firmly established that nr-axSpA and AS represent one single disease entity because differences between the two entities have been reported regarding gender, HLA-B27 status, burden of inflammation, clinical course, and response to anti-TNF treatment.³,¹⁸-²² A 35-year follow-up study of a cohort of patients with axSpA and their first-degree relatives revealed considerable heterogeneity of axSpA.²³ One of its major findings was a divergence between AS and nr-axSpA in sex ratios, with a male:female ratio of 2.5:1 for AS, compared to 1:1 for nr-axSpA. Moreover, although data on progression are limited, it appears that not all patients who are diagnosed with nr-axSpA progress to AS, and it may be too early to accept the concept that axSpA is one disease with a spectrum from nr-axSpA to radiographic-axSpA (AS).

A study reported that only a minority (26%) of patients with nr-axSpA progressed to AS when followed for up to 15 years.²⁴ These authors have therefore stated that the classification criteria for nr-axSpA identifies many patients who are unlikely to progress to AS, and they have proposed that nr-axSpA is a prolonged prodromal state that requires longer follow-up to document its evolvement to AS.²⁴ It has been suggested that nr-axSpA may represent an early stage of AS but may also just be an abortive form of a disease which does cause much pain but which may also never lead to structural changes of the axial skeleton.²⁵ Moreover, the cut-off between nr-axSpA and AS seems artificial and unreliable, and therefore the term nr-axSpA is much more important for classification than to diagnose patients with axSpA.²⁵ A latent class and transition analysis conducted in two early axSpA cohorts revealed that there is a considerable overlap between axSpA and peripheral SpA, larger than expected when the ASAS criteria were developed.²⁶ This analysis, additionally, identified a group of patients representing a grey zone, called axial SpA at risk. Of these individuals ≥ 84% fulfilled the ASAS criteria, although they were considered to neither have SpA nor to ever develop it.²⁶

Incidentally, the EMA approved the use of three TNF inhibitors (etanercept, adalimumab, and certolizumab) for the treatment of patients with nr-axSpA following the initial phase 3 trials conducted in this patient population. However, in United States, the FDA raised several key concerns, such as the uncertainty in the long-term clinical course of this entity and potential misdiagnosis of nr-axSpA in patients with fibromyalgia in the absence of objective signs of inflammation, and did not approve initial applications of adalimumab and certolizumab for the treatment of nr-axSpA.²⁷ The FDA has later approved certolizumab pegol, secukinumab, and ixekizumab for the treatment of nr-axSpA, based on clinical trials which addressed and resolved the key issues raised by the FDA.²⁸-³⁰

However, due to the absence of any diagnostic criteria for AS/axSpA, clinicians sometimes inappropriately use the classification criteria for diagnosis. This was unfortunately perpetuated in part by the statement in the abstract of the original paper describing the validation and final selection of the ASAS classification criteria for axSpA that stated that these criteria may help rheumatologists in clinical practice in diagnosing axSpA in those with chronic back pain.¹⁴ A recent international survey performed in five countries demonstrated that a substantial majority of rheumatologists are using the classification criteria for diagnostic purpose, while 40% rheumatologists think that the criteria need to be modified.³¹ It is of utmost importance to emphasize that the classification criteria and diagnostic criteria differ in several aspects (Table 2.6).¹³

The diagnostic approach is aimed at the estimation of the probability of a suspected disease, whereas the classification approach should be applied to patients with an established diagnosis to define a group, eg, for clinical and genetic research (Table 2.7).³² To establish the diagnosis of a disease in clinical practice, we need to exclude other conditions that may explain the patient’s symptoms, and such exclusions are not included in the ASAS classification criteria. As clinicians we make decisions about likelihood of a diagnosis that is based on the patient’s clinical history, physical examination, investigations and exclusion of alternative explanations. This decision is not based on whether the patient fulfills the classification criteria. It is hoped that, in near future, advances in our understanding of the biology of axSpA via novel imaging, genetic and biomarker studies will enable the resolution of many current issues in axSpA diagnosis and classification.³³

REFERENCES

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2.Sieper J, Rudwaleit M, Khan MA, Braun J. Concepts and epidemiology of spondyloarthritis. Best Pract Res Clin Rheumatol. 2006;20(3):401-417.

3.van Tubergen A. The changing clinical picture and epidemiology of spondyloarthritis. Nat Rev Rheumatol. 2015;11(2):110-118.

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